Human interferon, a kind of cytokine, is a protein that inhibits proliferation of viruses, cancer cells and the like via activation of immune responses in the body and apoptosis of cancer cells. Based on the type of cell that produces the interferon, interferons are divided into three subclasses i.e., interferon alpha, interferon beta, and interferon gamma. In particular, interferon alpha is produced by B lymphocyte, null lymphocyte, and macrophage, and has antiviral and antitumor activities, activates the NK (Nature Killer) cell, and has a suppressive nature on bone marrow cells.
Recently, clinical studies have reported that recombinant human interferon alpha has therapeutic potential for the treatment of a wide variety of solid tumors, and two types of interferons prepared by recombinant DNA technology are commercially available (interferon α-2b recombinant (Intron-A, Schering Corp.); interferon α-2a recombinant (Roferon, Hoffmann-La Roche, Inc.)). Intron A is indicated for use in the treatment of malignant melanoma in combination with surgery, aggressive follicular Non-Hodgkin's Lymphoma in combination with anthracycline chemotherapy, intralesional treatment of condylomata acuminata, hairy cell leukemia, and AIDS-related Kaposi's sarcoma. Roferon is indicated for use in the treatment of Philadelphia chromosome positive chronic myelogenous leukemia (CML) and AIDS-related Kaposi's sarcoma. They are also known to be effective for bladder cancer (Torti, F. M. et al., J. clin. Onco., 3, 506-512, 1985) and renal cancer (Vugrin, D. et al., Cancer treat. Rep., 69, 817-820, 1985). Recently, interferon modified with polyethylene glycol (PEG) has been approved for use in the treatment of malignant melanoma. However, native interferon alpha or PEG-modified interferon alpha has been reported to show low anti-cancer effects because of a short half-life and low efficacy.
Cancer is an abnormal growth of cells caused by multiple changes in gene expression leading to a deregulated balance of cell proliferation and cell death, that invades and destroys nearby tissues, metastasizes to distant sites, eventually leads to death. It has been known that cancer cells abnormally divide and differentiate, arise in any tissue within the body, and are caused by a single factor or combinations thereof. These factors are environmental factors such as a wide variety of chemicals or radiation, infectious diseases such as viral infections, and hereditary factors. Cancer can be classified into several hundred types according to the organs involved and cells constituting cancer tissue.
For the treatment of cancer, surgery, radiation therapy, and chemotherapy have been used, but chemotherapy and radiation therapy have the problem of severe side effects such as vomiting and nausea, cytopenia, infection, cachexia, mucositis, hair loss, etc. In particular, the side effects of chemotherapy can dramatically affect the patient's life, and rapidly reduce the treatment compliance of patients.
Meanwhile, pancreatic cancer has a poor prognosis with a 5-year survival rate of less than 5%. Because pancreatic cancer is usually found in an advanced stage, less than 20% of patients are eligible for surgery. Despite resection, micro-metastasis and lymph nodal recurrence occur in up to 50% of patients mostly within 2 years. Pancreatic cancer is known to be one of the most lethal cancers among all gastrointestinal cancers, and it is a malignant tumor that ranks as the fourth commonest cause of cancer death in Western countries, and the sixth in Korea. Even though pancreatic cancer accounts for only 2-3% of all cancer patients, it accounts for 6% of all cancer-related deaths. Regardless of the type of chemotherapy, locally-advanced pancreatic cancer and metastatic pancreatic cancer have a median survival of 8-12 months and 3-6 months, respectively, and thus pancreatic cancer is very lethal.
A current powerful therapeutic strategy for advanced pancreatic cancer is intravenous administration of 2′-deoxycytidine nucleoside analogue, gemcitabine (Lilly) that is able to induce death of human pancreatic cancer cells and inhibit tumor growth and progression. However, a single administration of gemcitabine shows efficacy as low as a median overall survival of 5.7 months. Recently, erlotinib (Tarceva) in combination with gemcitabine has been approved for metastatic pancreatic cancer, and combination therapy of gemcitabine and erlotinib increased the 1-year survival rate of pancreatic cancer patients from 18% to 24%, compared to single administration of gemcitabine. However, an important factor of chemotherapy, median overall survival was increased only by 0.33 months. Erlotinib is a low molecular weight, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and does not distinguish cancer cells from rapidly dividing normal cells. Thus, it shows higher toxicity than a single administration of gemcitabine, and generates resistance upon long-term exposure.
For this reason, combination therapies of gemcitabine/interferon alpha, gemcitabine/cisplatin, gemcitabine/capecitabine, and gemcitabine/avastin have been attempted, in addition to the combination of gemcitabine and erlotinib. However, the therapeutic effects are not satisfactory.